It is recently evident that the central nervous system (CNS) exerts important regulatory influences on gastrointestinal (GI) motility. CNS neuropeptides appera to be especially important in central regulation of motility. Certain of the centrally-distributed "brain-gut" neuropeptides administered exogenously have dramatic effects on the motility and reflexes of the GI tract. The specific sites or mechanisms through which these peptides affect the gut have not been determined. Neuropeptides can act at 4 discrete sites in affecting GI motor function: the brain, the neurons of the enteric nervous system, the smooth muscle of the gut, and, as only very recently demonstrated, the spinal cord. It is the hypothesis of this proposal that the "brain-gut" peptides act through chemosensitive sites in the brain and spinal cord to serve as physiological or pharmacological modulators of GI motility. We propose to focus our studies on the central effects of mammalian bombesin (gastrin releasing peptide; GRP), thyrotropin releasing hormone and certain opioid neuropeptides on (a) ongoing and (b) evoked reflex activity of the gut. Our approach will initially involve administration of neuropeptides into the brain and into the spinal subarachnoid space to define the chemosensitive sites fundamentally involved in the control of GI motility. The endpoints to be studied are all standard in our laboratory and include determination of gastric emptying and small and large bowel transit, stomach and intestinal intraluminal pressure in the rat as well as GI transit in the mouse. In addition, a recently developed model proposed for study is the evoked gastrocolic reflex in the rat. The major techniques that will be employed to dissect the peptidergic pathways that control the gut include: (a) microinjections into specific brain locations and cord levels and (b) transection of the spinal cord at various levels so that the influence of the sympathetic or parasympathetic gut innervation can be determined. Our recent work provides evidence that peptide sensitive sites in the spinal cord can be distinguished anatomically, pharmacologically and functionally from those in the brain. Knowledge of the sites and functions of the neuronal "brain-gut" peptides will provide new information about central nervous system-gut interactions.